Pharmacometric Approaches for Extrapolation from Adult to Pediatric T2DM Tarek Leil, PhD Satyendra Suryawanshi, MPharm, PhD Ronald Portman, MD BMS Pediatric Center of Excellence
Conceptual Framework Sequential steps of extrapolation Basic prerequisite: - similarity of disease / progression - similarity of response to treatment 1. Extrapolation concept a. Biological/pharmacological rationale b. Quantitative evidence Pharmacometric c. Hypothesis/model building Models Adapting Learning 2. Extrapolation plan -Reduction of data requirements Clinical Trial Simulation 3. Validation Innovative Trial Design
Definition of Diabetes (adult and pediatric) per American Diabetes Association: Similarity of Disease 1. HbA1c ≥ 6.5% (test performed in a certified laboratory); or 2. Fasting (defined as no caloric intake for at least 8 hours) plasma glucose ≥ 126 mg/dl (7.0 mmol/L); or 3. 2- hour plasma glucose ≥200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test performed as described by the World Health Organization by using a glucose load containing the equivalent of 75g anhydrous glucose dissolved in water; or 4. A random plasma glucose ≥200 mg/dl (11.1 mmol/L) with symptoms of hyperglycemia. Pediatrics 2013;131:364-382
Type 2 Diabetes in Pediatrics and Adults: Thoughts from a Clinical Pharmacology Perspective JAYABHARATHI VAIDYANATHAN, SALLY CHOE, CHANDRAHAS G. SAHAJWALLA Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration 2012; J Pharm Sci 101:1659–1671, 2012 Mechanism PK PD Comments Biguanide ; ↓ Metformin Adult and pediatric Adult and pediatric Decrease in body wgt; ↓ Pinsulin , ↓ similar reduction in hepatic glucose similar HgbA1c & FPG production; ↑ insulin resistance, TODAY 51% pts insulin sensitivity well-controlled; AE difficult to achieve full dose PPAR γ Rosiglitizone Adult and pediatric Adult and pediatric Did not reach non- similar inferiority with similar metformin, side effect of wgt gain in pediatrics Glimepiride Insulin Adult and pediatric Less effective but Did not demonstrate only 50% of adult non-inferiority with secretagogue similar dose used metformin Glyburide/metformin combination Adult and pediatric Less effective in kids Naïve patients in than adults but lower adult and kids had glucovance similar starting HbA1c in better response kids and effect greatest in adult >9% Similarity of drug PK/PD in adult and pediatric T2DM
Potential Approach to Extrapolation of T2DM: DPP-4 Inhibitor Example • Integrate prior clinical data on DPP-4 inhibitors using a pharmacometric model • Understand assumptions of model Integrate • Similar mechanism of action • Make adjustments to model to account for potential differences in pediatric subjects • Extrapolate PK/PD and clinical outcomes in pediatric trial Extrapolate • Optimize design of first pediatric trial • Conduct clinical trial to validate predictions from quantitative model • Adjust understanding of pediatric PK/PD or clinical Validate outcome if necessary Maximize Utilization of Prior Knowledge
Integration of Clinical Data on DPP-4 Inhibitors Pharmacometric Model Incorporating PK, DPP-4 inhibition and HbA1c* DPP-4 Inhibitor No. Trials No. Patients WAI = predicted weighted Saxagliptin 2 1315 average inhibition Alogliptin 5 2106 Sitagliptin 12 5970 Vidagliptin 14 4447 Total 33 13838 *Gibbs JP, Fredrickson J, Barbee T, Correa I, Smith B, Lin SL, Gibbs MA. Quantitative model of the relationship between dipeptidyl peptidase-4 (DPP-4) inhibition and response: meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results. J Clin Pharmacol. 2012 Oct;52(10):1494-505. Epub 2011 Dec 12.
Evaluate Potential Approaches to Validate Extrapolation Example 1 : PK/PD study followed by long term safety study (model if no need to validate efficacy) 1 Wk Validate PK & DPP-4 1:1:1 Conduct 52 week add- Extrapolation Randomization on to metformin safety Placebo study with HbA1c as Select Optimal Pediatric DPP4I 5 mg 2º Endpoint Dose using PK and DPP-4 DPP4I 2.5 mg Inhibition Example 2 : Confirmatory efficacy study powered for dose-response as add-on therapy to metformin followed by long term safety extension 1:1:1 Select Optimal Pediatric 12-24* Wk Randomization Dose using dose/exposure – response for HbA1c Placebo 52 wk extension for safety assessment Metformin DPP4I 2.5 mg Lead-In Period DPP4I 5.0 mg Collect data to validate PK, DPP-4, and Efficacy (HbA1c) Extrapolation Any alternative pediatric study designs may be evaluated using clinical trial simulations *simulation performed for 24 weeks
Exploration of Power/Sample Size using Clinical Trial Simulations Relationship with High Confidence* Power to Estimate Dose-Response Efficacy < Adult Efficacy = Adult 120 Potency < Adult 100 80 60 40 20 0 120 Potency = Adult 100 80 60 40 20 0 0 20 40 60 80 100 0 20 40 60 80 100 Sample Size Per Treatment Arm To achieve ~ 80% power: total sample size of 51 (efficacy/potency equivalent to adult) to 120 (low efficacy and potency) Total sample size of N = 90 subjects: power of ~ 70% (low efficacy and potency) to 93% (efficacy/potency equivalent to adult) *95% confidence interval for estimate of placebo anchored dose-response slope does not include zero.
Summary: Quantitative Integration, Extrapolation and Confirmation Pre-Clinical Clinical Drug Development Drug Development Target discovery Lead optimization Pre-clinical Pharmacology Integrate Phase I Phase II Extrapolate Confirm Phase III • Pharmacometric models can be used to facilitate quantitative integration and extrapolation from adult to pediatric subjects • Robust models exist for DPP-4 inhibitors to support extrapolation for T2DM
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Pharmacometrics Facilitates Quantitative Extrapolation Prior Knowledge from Adult Trials, Preclinical Data and Literature Pharmacometric Adult Phase 1 Data Model (PK/PD, Pediatric Intrinsic/Extrinsic Investigation PK/PD Effects) Dose selection Biomarker Adult Patient Data selection (Efficacy/Safety) Sample size Power Literature Inclusion/exclusion (Clinical & Pre-Clinical criteria Data from Similar MoA) Quantitative Integration of Prior Evidence Hypothesis evaluation Pre-Clinical (Target/Disease Extrapolation Biology)
Extrapolation from Adult to Pediatric for Saxagliptin for Trial Simulation Oral Dose Peripheral Compartment Vp Q m Q p Non-Renal Potency adjusted CL Total Active Moiety Active Metabolite Saxagliptin (nM) DPP-4 BMS-510849 CYP Enzyme Central Compartment Vc Weighted Avg. Inhibition Renal CL p Renal CL m HbA1c Age & Body Size Adjustment of DPP-4 Adjustment of PK PD for Age/Disease (WT/75) 0.75 ED 50 AGE 0.83 /(0.31+AGE 0.83 ) EMax (CrCL/82.8) 1.28 ~Saxa, (CrCL/82.8) 0.44 ~Metabolite
Application of Pharmacometric Model in Pediatric Trial Design High Potency Low Potency High Efficacy Exposure-response model for Candesartan and Metoprolol in pediatric subjects Low Efficacy Clinical Trial Simulation Test different assumptions of drug potency/efficacy on power & sample size for a dose-response trial AAPS J. 2013 Jan 10. [Epub ahead of print
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